Osteoclasts are multinuclear cells of hematopoietic lineage, which function in the process of bone resorption. Typically, bone resorption proceeds through osteoclast adherence to a bone surface and formation of a tight sealing zone. This activity is followed by extensive membrane ruffling on the surface of the osteoclasts. Such action creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way a resorption pit is formed. At the completion of this cycle osteoblasts remodel the bone; that is, they deposit a new protein matrix that is subsequently mineralized at this zone.
Normally, a balance exists between the processes of bone resorption and new bone formation during remodeling. This normal balance of bone resorption and bone formation, however, may be disrupted resulting in a net loss of bone in each cycle of remodeling. Osteoporosis is a reduction in the quantity of bone or atrophy of skeletal tissue. Osteoporosis is characterized by reduced bone mass and disruptions in the microarchitecture of the bone. These characteristics may lead to fractures, which can result from a minimal amount of trauma. Typical sites of fractures include vertebral bodies, distal radius, and the proximal femur. However, because those suffering from osteoporosis have general skeletal weakness, fractures may occur at other sites.
Since osteoporosis is characterized by an increase in bone resorption with respect to bone remodeling, therapeutic agents that suppress bone resorption should provide a suitable treatment for osteoporosis. Administration of estrogens or calcitonin has been the bone resorption suppression treatment typically employed. However, these treatments do not always achieve the desired effect. Consequently, there is a continuing need for therapeutic agents which can attentuate bone resorption in a subject in need of such attenuation.
Cathepsin K, which has also been called cathepsin O, cathepsin O2, and cathepsin X, is a member of the cysteine cathepsin family of enzymes, which are part of the papain superfamily of cysteine proteases. Other distinct cysteine protease cathepsins, designated cathepsin B, cathepsin C, cathepsin F, cathepsin H, cathepsin L, cathepsin S, cathepsin V (also called L2), cathepsin W, & cathepsin Z (also called cathepsin X), have also been described in the literature. Cathepsin K polypeptide and the cDNA encoding such polypeptide are discussed in U.S. Pat. No. 5,501,969. A crystal structure for cathepsin K is disclosed in PCT Patent Application WO 97/16177, published May 9, 1997. Cathepsin K is abundantly expressed in osteoclasts under normal conditions and may be the major cysteine protease present in these cells. See, Tezuka, et al., J. Biol. Chem., 1994, 269, 1106; Inaoka, et al, Biochem. Biophys. Res. Commun., 1995, 206, 89; and Shi, et al., FEBS Lett., 1995, 357,129. This abundant selective expression of cathepsin K in osteoclasts suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, such as osteoporosis.
The selective inhibition of cathepsin K may also be useful in treating other diseases and conditions. Such disorders include autoimmune diseases such as rheumatoid arthritis, osteoarthritis, neoplastic diseases, parasitic diseases, and atherosclerosis. For instance, cathepsin K is expressed in the synovium and synovial bone destruction sites of patients with rheumatoid arthritis. See Votta, B. J. et al.; J. Bone Miner. Res. 1997, 12, 1396; Hummel, K. M. et al., J. Rheumatol. 1998, 25, 1887; Nakagawa, T. Y. et al., Immunity 1999, 10, 207; Otsuka, T. et al., J. Antibiot. 1999, 52, 542; Li, Z. et al, Biochemistry 2000, 39, 529; Diaz, A. et al., Mol. Med. 2000, 6, 648; Moran, M. T. et al., Blood 2000, 96, 1969.
Cathepsin K levels are elevated in chondroclasts of osteoarthritic synovium See Dodds, R. A. et al., Arthritis Rheum. 1999, 42, 1588; Lang, A. et al., J. Rheumatol 2000, 27, 1970).
Neoplastic cells also have been shown to express cathepsin K. See, Littlewood-Evans, A. J. et al., Cancer Res. 1997, 57, 5386; Komarova, E. A., et al., Oncogene 1998, 17, 1089; Santamaria, I., et al., Cancer Res. 1998, 58, 1624; Blagosklonny, M. V. et al., Oncogene 1999, 18, 6460; Kirschke, H. et al., Eur. J. Cancer 2000, 36, 787; Zhu, D.-M. et al., Clin. Cancer Res. 2000, 6, 2064.
Cysteine protease inhibitors have been suggested as chemotherapy for parasitic diseases. See, McKerrow, J. H. Int. J. Parasitol 1999, 29, 833; Selzer, P. M. et al., Proc. Natl. Acad. Sci 1999, 96, 11015; Caffrey, C. R. et al., Curr. Drug Targets 2000, 1, 155; Du, X. et al., Chem. Biol. 2000, 7, 733; Hanspal, M. Biochim. Biophys. Acta 2000, 1493, 242; Werbovetz, K. A. Curr. Med. Chem 2000, 7, 835.
Elastolytic cathepsins S and K are shown to be expressed in human atheroma. See, Sukhova, G. K. et al., J. Clin. Invest 1998, 102, 576–583; Parks, W. C. J. Clin. Invest 1999, 104, 1167; Shi, G.-P. et al., J. Clin. Invest 1999, 104, 1191; Cao, H. et al., J. Hum. Genet 2000, 45, 94.
The present inventors have now discovered novel ketone derivative compounds, which are inhibitors of serine and cysteine protease activities, more particularly, cathepsin family cysteine protease activities, and most particularly, cathepsin K activity. Such ketone derivatives are useful in the treatment of disorders associated with serine and cysteine protease activity, including osteoporosis, Paget's disease, hypercalcemia of malignancy, metabolic bone disease, osteoarthritis, rheumatoid arthritis, periodontitis, gingivitis, atherosclerosis, and neoplastic diseases associated with cathepsin K activity.